Ischemia is a deficiency of blood in tissue, and is a significant medical problem. For example, heart disease is a leading cause of morbidity and mortality and two related conditions which are of significant concern are myocardial ischemia (tissue anemia in the heart muscle as a result of obstruction of the blood supply such as by vasoconstriction), and myocardial infarct or infarction (an ischemic condition resulting in the localized death of heart muscle and caused by the particulate obstruction of the flow of arterial blood). While progress has been made in the treatment of ischemic tissue, there is much room for improvement.
One problem with potential antiischemic agents is the action of these agents on other than ischemic tissue. For example, many potent coronary vasodilators are ineffective during myocardial ischemia because they dilate nonischemic coronary blood vessels as well as the ischemic vessels, which draws blood flow away from the ischemic zone. Additionally, many antiischemic compounds (e.g., calcium entry blockers) would be more effective if the agent could be targeted directly to the ischemic region.
Thus, it has been a desideratum to provide a drug delivery system to selectively deliver a compound into an ischemic myocardial bed, that is, deliver an active agent preferentially to infarcted heart tissue rather than nonischemic tissue. In this regard, the terms "ischemic" or "ischemia" as used herein refer to tissue in the state of traumatic tissue anemia and include infarcted tissue.
Phospholipid vesicles (liposomes) have been pursued in the hope that they would concentrate in selected tissues and result in additional enhancement in the delivery of active agents from this tissue specificity. Accordingly, workers have attempted to employ liposomes for the delivery of active agents to myocardial tissue. For example, in a publication by Caride and Zaret in Science 198, 735-738 (1977) multilamellar liposomes of approximately 1,000 nm in diameter with either net positive, negative or neutral charge were administered to mammals after the induction of embolic closed-chest interior wall myocardial infarction. The liposomes were labeled with .sup.99m Tc-DTPA (Diethylene triamine pentaacetic acid). While this publication reports an accumulation of positive and neutral MLVs in infarcted myocardial tissue, free .sup.99m Tc-DTPA has been shown to accumulate in ischemic myocardium (ten times that of normal myocardium after a circulation time of one hour) and further data has shown that the accumulation of .sup.99m Tc-DTPA in infarcted myocardium observed in the subject reference was actually due to the release of vesicle contents in circulation and subsequent accumulation of free .sup.99m Tc-DTPA in the damaged myocardium.
The publication by Mueller et al. in Circulation Research 49, 405-415 (1981) reports the use of a protein marker (.sup.131 I-albumin) retained in 400 to 700 nanometer small, unilamellar liposomes. The results show a slight accumulation of positive liposomes in ischemic myocardium compared to normal myocardium (ischemic/normal equal 1.38:1) and no net accumulation in ischemic myocardium was seen with neutral liposomes (ratio 0.81:1).
An article in Cardiovascular Research 16, 516-523 (1982) Cole et al. describes myocardial liposome uptake in the early stages of myocardial infarction and concluded that 75 to 125 nm liposomes show no evidence of preferential uptake by ischemic myocardium. The authors suggest that liposomes thus have limited potential as a means of drag delivery in myocardial infarction. Antibodies have also been covalently bound to liposomes in an attempt to deliver such vesicles preferentially to certain tissues, but the results have been less than successful in many instances.